Publication: Modulación del sistema endocannabinoide como herramienta terapéutica en esclerosis múltiple: efecto sobre los condroitín sulfato proteoglicanos
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2018-11-05
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Universidad Complutense de Madrid
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Abstract
La esclerosis múltiple (EM) es una enfermedad inflamatoria desmielinizante y neurodegenerativa que afecta al sistema nervioso central (SNC) y que evoluciona de manera crónica hacia un declive neurológico progresivo desembocando en incapacidad permanente. A nivel histopatológico, la EM se caracteriza por presentar áreas multifocales de inflamación, desmielinización y daño axonal en la sustancia blanca del SNC que da lugar a la formación de lesiones donde se observan cicatrices glióticas crónicas con proliferación astrocítica. En la EM junto con los procesos de desmielinización, tienen lugar procesos de reparación y remielinización, sin embargo, conforme la enfermedad progresa la remielinización resulta menos eficiente, cronificándose los déficits neurológicos con el desarrollo de la patología. Este fallo en la remielinización no parece ser debido a una ausencia de precursores de oligodendrocitos (OPCs) en la zona de lesión, sino más bien a problemas en su diferenciación. Se ha apuntado a la presencia de factores inhibitorios en las zonas desmielinizadas como los responsables de impedir la diferenciación de los OPCs entre los que se encuentran las proteínas denominadas condroitín sulfato proteoglicanos (CSPGs). Los CSPGs son unas macromoléculas que forman parte de la matriz extracelular (ECM) y la cicatriz glial y son consideradas factores determinantes del fallo en la remielinización y la regeneración axonal generando un ambiente no permisivo que limita la diferenciación de los OPCs y la supervivencia neuronal. El modelo del virus de Theiler resulta especialmente adecuado para analizar aspectos de la formación de la cicatriz glial en lesiones inflamatorias y desmielinizantes y en la remielinización. El proceso de desmielinización durante la fase crónica del modelo de TMEV se ve acompañado por alteraciones en la ECM, como la acumulación de CSPGs y astrogliosis reactiva. Además, la limitada remielinización observada en el modelo se ha asociado a una insuficiente diferenciación de OPCs. Los cannabinoides han demostrado aliviar algunos aspectos de la sintomatología de la EM. Mientras que en modelos de EM los cannabinoides presentan propiedades antioxidantes, antiexcitotóxicas y neuroprotectoras y mejoran la remielinización, promoviendo la diferenciación de los OPCs, poco se sabe sobre sus efectos sobre las proteínas de matriz extracelular y en particular sobre los CSPGs...
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease that affects the central nervous system (CNS) and leads to a neurological decline and permanent disability. The pathologic hallmarks in MS include multifocal areas of inflammation, demyelination and axonal damage in the brain and spinal cord white matter that are also present in the gray matter at cortical levels and leads to the formation of lesions where gliotic scars with astrocytic proliferation are observed. In MS, repair and remyelination processes occur spontaneously following demyelinating phases, but, as the disease progresses, remyelination becomes less efficient leading to increased disability in patients. The failure in remyelination does not seem to be due to an insufficient number of oligodendrocyte precursor cells (OPCs) in the lesion site but a failure in their differentiation. There are different inhibitory molecules present in demyelinated areas that impede OPCs differentiation, among these, we can find the chondroitin sulphate proteoglycans (CSPGs). CSPGs are extracellular matrix proteins (ECM) that have been reported to accumulate in MS lesions and are considered important factors for the failure of remyelination and regeneration through the creation of a non-permissive environment that limits attachment, survival and differentiation of OPCs as well as neuron survival. Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is an experimental viral model of MS suitable to elucidate the role of glial scar formation in chronic inflammatory and demyelinating CNS lesions. The limited remyelination observed in TMEVIDD has been associated to insufficient oligodendroglial differentiation. Moreover, the chronic demyelination is accompanied by astrogliosis and alterations in spinal cord ECM and accumulation of CSPGs which in turn may contribute to the failure of axon remyelination and regeneration. Cannabinoids are currently being studied for their potential benefits in the treatment of MS and other neuroinflammatory/neurodegenerative diseases. Although preclinical studies have demonstrated that cannabinoids can alleviate MS-associated symptoms like spasticity and exhibit anti-inflammatory, antioxidant, anti-excitotoxic properties and promote remyelination and differentiation of OPCs there is no evidence about their role over extracellular matrix proteins and CSPGs...
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease that affects the central nervous system (CNS) and leads to a neurological decline and permanent disability. The pathologic hallmarks in MS include multifocal areas of inflammation, demyelination and axonal damage in the brain and spinal cord white matter that are also present in the gray matter at cortical levels and leads to the formation of lesions where gliotic scars with astrocytic proliferation are observed. In MS, repair and remyelination processes occur spontaneously following demyelinating phases, but, as the disease progresses, remyelination becomes less efficient leading to increased disability in patients. The failure in remyelination does not seem to be due to an insufficient number of oligodendrocyte precursor cells (OPCs) in the lesion site but a failure in their differentiation. There are different inhibitory molecules present in demyelinated areas that impede OPCs differentiation, among these, we can find the chondroitin sulphate proteoglycans (CSPGs). CSPGs are extracellular matrix proteins (ECM) that have been reported to accumulate in MS lesions and are considered important factors for the failure of remyelination and regeneration through the creation of a non-permissive environment that limits attachment, survival and differentiation of OPCs as well as neuron survival. Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is an experimental viral model of MS suitable to elucidate the role of glial scar formation in chronic inflammatory and demyelinating CNS lesions. The limited remyelination observed in TMEVIDD has been associated to insufficient oligodendroglial differentiation. Moreover, the chronic demyelination is accompanied by astrogliosis and alterations in spinal cord ECM and accumulation of CSPGs which in turn may contribute to the failure of axon remyelination and regeneration. Cannabinoids are currently being studied for their potential benefits in the treatment of MS and other neuroinflammatory/neurodegenerative diseases. Although preclinical studies have demonstrated that cannabinoids can alleviate MS-associated symptoms like spasticity and exhibit anti-inflammatory, antioxidant, anti-excitotoxic properties and promote remyelination and differentiation of OPCs there is no evidence about their role over extracellular matrix proteins and CSPGs...
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Tesis de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 12/03/2018